Fundamental biologic processes of aging including epigenetic alterations underlie risk for onset of multiple age-related diseases and degenerative conditions. The most studied epigenetic mark is DNA methylation, which changes with age and is likely to be involved with aging processes and susceptibility to age-related disease. Epigenome-wide association studies (EWAS) have proliferated in recent years, but due to the use of small cross-sectional samples and a lack of consensus on study design and analysis, results have been inconsistent. In fact, among the many diseases and traits studied in EWAS, age is one of the few that robustly associates with DNA methylation across studies. Since age is a major risk factor for most chronic diseases, this suggests DNA methylation and other epigenetic factors as possible mechanisms linking age to disease risk. The long-term goal of this collaborative effort is to characterize the epigenetics underlying aging as a risk factor for age-related diseases and conditions, with a focus on cardiovascular disease, type 2 diabetes, frailty, and sarcopenia, which share underlying risk factors and are selected based on their high burden of disease and resultant disability and mortality in older adults. The planning phase proposed here will lay the groundwork for a well-powered consortium of large human cohort studies that will avoid the pitfalls of earlier studies through careful design. The goals of this proposal are thus to design a comprehensive longitudinal study to identify epigenetic changes that mediate the relationship between age and risk for chronic diseases and degenerative conditions, and to determine the appropriate timeline, support, and infrastructure necessary for such a study. We have a unique opportunity to achieve these goals, because we can leverage and build on existing infrastructure from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium that includes longitudinal deeply phenotyped cohorts with existing DNA methylation data for >15,000 participants as well as >100,000 banked longitudinal bio specimens. Aims 1 and 2 will focus on planning and piloting novel analytic methods and epigenomic technologies to guide our selection of longitudinal cohorts, clinical phenotypes, epigenetic factors, tissues, and statistical methods. Aim 3 proposes meetings, workshops, and interaction with leading experts to coordinate and refine the translation of results from Aims 1 and 2 into design of our future study. Completion of these aims will position us to carry out an extremely powerful study to implicate epigenetic changes driving age-related risk for disease; such findings will have both diagnostic and predictive value, and will contribute to our understanding of epigenetic mechanisms underlying aging as a risk factor for cardiovascular disease, diabetes, frailty, and sarcopenia. Identifying the epigenetic factors that modify age-related disease risk may provide novel preventative and therapeutic targets to slow aging and increase health span by delaying onset of multiple diseases so that older adults can live a long and healthy life.